Article: Bradykinin and high glucose promote renal tubular inflammation
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- Publisher Website: 10.1093/ndt/gfp599
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- PMID: 19923143
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| Title | Bradykinin and high glucose promote renal tubular inflammation |
|---|---|
| Authors | Tang, SCW1 Chan, LYY1 Leung, JCK1 Cheng, AS1 Chan, KW1 Lan, HY1 Lai, KN1 |
| Keywords | Bradykinin Chemokines Diabetic nephropathy High glucose Kallirein |
| Issue Date | 2010 |
| Publisher | Oxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/ |
| Citation | Nephrology Dialysis Transplantation, 2010, v. 25 n. 3, p. 698-710 [How to Cite?] DOI: http://dx.doi.org/10.1093/ndt/gfp599 |
| Abstract | Background. The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.Methods and Results. High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF) and B2K receptor (B2KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-β mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-β, whereas inhibition of PKC by staurosporine partially reduced HG-but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-β expression. The B2KR blocker, icatibant, downregulated BK-and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG-and BK-induced IL-6, CCL-2 and TGF-β secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, attenuated HG-induced PKC but not HG-or BK-induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-β secretion. Rosiglitazone plus icatibant further reduced these effects of HG.Conclusions. In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B2KR blockade and PPAR-γ activation deserves clinical investigation. |
| ISSN | 0931-0509 2011 Impact Factor: 3.396 2011 SCImago Journal Rankings: 0.277 |
| DOI | http://dx.doi.org/10.1093/ndt/gfp599 |
| References | References in Scopus |
| dc.contributor.author | Tang, SCW | ||||
|---|---|---|---|---|---|
| dc.contributor.author | Chan, LYY | ||||
| dc.contributor.author | Leung, JCK | ||||
| dc.contributor.author | Cheng, AS | ||||
| dc.contributor.author | Chan, KW | ||||
| dc.contributor.author | Lan, HY | ||||
| dc.contributor.author | Lai, KN | ||||
| dc.date.accessioned | 2010-08-12T04:36:57Z | ||||
| dc.date.available | 2010-08-12T04:36:57Z | ||||
| dc.date.issued | 2010 | ||||
| dc.description.abstract | Background. The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.Methods and Results. High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF) and B2K receptor (B2KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-β mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-β, whereas inhibition of PKC by staurosporine partially reduced HG-but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-β expression. The B2KR blocker, icatibant, downregulated BK-and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG-and BK-induced IL-6, CCL-2 and TGF-β secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, attenuated HG-induced PKC but not HG-or BK-induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-β secretion. Rosiglitazone plus icatibant further reduced these effects of HG.Conclusions. In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B2KR blockade and PPAR-γ activation deserves clinical investigation. | ||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||
| dc.identifier.citation | Nephrology Dialysis Transplantation, 2010, v. 25 n. 3, p. 698-710 [How to Cite?] DOI: http://dx.doi.org/10.1093/ndt/gfp599 | ||||
| dc.identifier.citeulike | 6185871 | ||||
| dc.identifier.doi | http://dx.doi.org/10.1093/ndt/gfp599 | ||||
| dc.identifier.epage | 710 | ||||
| dc.identifier.hkuros | 174356 | ||||
| dc.identifier.isi | WOS:000274987800012
Funding Information: This work was supported by the Research Grants Council (General Research Fund ref HKU 7764/07M) of Hong Kong. Part of the data contained in this study was presented in abstract form at the American Society of Nephrology Annual Meeting and Scientific Exposition, November 6-9, 2008, Philadelphia, PA, USA. Icatibant was a kind gift from Sanofi-Aventis Deutschland GmbH. Rosiglitazone was a kind gift from GlaxoSmithKline (Compound Management Division, Stevenage, Herts, UK). | ||||
| dc.identifier.issn | 0931-0509 2011 Impact Factor: 3.396 2011 SCImago Journal Rankings: 0.277 | ||||
| dc.identifier.issue | 3 | ||||
| dc.identifier.openurl | | ||||
| dc.identifier.pmid | 19923143 | ||||
| dc.identifier.scopus | eid_2-s2.0-77649226697 | ||||
| dc.identifier.spage | 698 | ||||
| dc.identifier.uri | http://hdl.handle.net/10722/65486 | ||||
| dc.identifier.volume | 25 | ||||
| dc.language | eng | ||||
| dc.publisher | Oxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/ | ||||
| dc.publisher.place | United Kingdom | ||||
| dc.relation.ispartof | Nephrology Dialysis Transplantation | ||||
| dc.relation.references | References in Scopus | ||||
| dc.rights | Nephrology, Dialysis, Transplantation. Copyright © Oxford University Press. | ||||
| dc.rights | This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nephrology, Dialysis, Transplantation following peer review. | ||||
| dc.subject.mesh | Bradykinin - physiology | ||||
| dc.subject.mesh | Diabetic Nephropathies - pathology - physiopathology | ||||
| dc.subject.mesh | Glucose - physiology | ||||
| dc.subject.mesh | Hyperglycemia - physiopathology | ||||
| dc.subject.mesh | Kidney Tubules, Proximal - pathology - physiopathology | ||||
| dc.subject | Bradykinin | ||||
| dc.subject | Chemokines | ||||
| dc.subject | Diabetic nephropathy | ||||
| dc.subject | High glucose | ||||
| dc.subject | Kallirein | ||||
| dc.title | Bradykinin and high glucose promote renal tubular inflammation | ||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong